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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.00597

Unveiling integrated functional pathways leading to enhanced respiratory disease associated with inactivated respiratory syncytial viral vaccine

 Sean (Xuguang) Li1, 2*,  Marsha S. Russell1, Marybeth Creskey1, Abenaya muralidharan1, 2, Changgui Li3, Jun Gao1, Wangxue Chen4, Louise Larocque1, Jessie R. Lavoie1, Aaron Farnsworth1, Michael Rosu-Myles1, Carole L. Yauk1, jingxin Cao5, Gary Van Domselaar5 and Terry Cyr1
  • 1Health Canada, Canada
  • 2University of Ottawa, Canada
  • 3National Institutes for Food and Drug Control (China), China
  • 4National Research Council Canada (NRC-CNRC), Canada
  • 5National Microbiology Laboratory, Canada

Respiratory syncytial virus (RSV) infection is a severe threat to young children and the elderly. Despite decades of research, no vaccine has been approved. Notably, instead of affording protection, a formalin-inactivated RSV vaccine induced severe respiratory disease including deaths in vaccinated children in a 1960s clinical trial; however, recent studies indicate that other forms of experimental vaccines can also induce pulmonary pathology in pre-clinical studies. These findings suggest that multiple factors/pathways could be involved in the development of enhanced respiratory diseases. Clearly, a better understanding of the mechanisms underlying such adverse reactions is critically important for the development of safe and efficacious vaccines against RSV infection, given the exponential growth of RSV vaccine clinical trials in recent years.

By employing an integrated systems biology approach in a pre-clinical cotton rat model, we unravelled a complex network of pulmonary canonical pathways leading to disease development in vaccinated animals upon subsequent RSV infections. Cytokines including IL-1, IL-6 GRO/IL-8 and IL-17 in conjunction with mobilized pulmonary inflammatory cells could play important roles in disease development, which involved a wide range of host responses including exacerbated pulmonary inflammation, oxidative stress, hyperreactivity and homeostatic imbalance between coagulation and fibrinolysis. Moreover, the observed elevated levels of MyD88 implicate the involvement of this critical signal transduction module as the central node of the inflammatory pathways leading to exacerbated pulmonary pathology. Finally, the immunopathological consequences of inactivated vaccine immunization and subsequent RSV exposure were further substantiated by histological analyses of these key proteins along with inflammatory cytokines, while hypercoagulation was supported by increased pulmonary fibrinogen/fibrin accompanied by reduced levels of plasma D-dimers.

Enhanced respiratory disease associated with inactivated RSV vaccine involves a complex network of host responses, resulting in significant pulmonary lesions and clinical manifestations such as tachypnea and airway obstruction. The mechanistic insight into the convergence of different signal pathways and identification of biomarkers could help facilitate the development of safe and effective RSV vaccine and formulation of new targeted interventions.

Keywords: RSV Vaccines, RSV vaccine-enhanced disease, Proteomics, systems biology, Hypercoagulation, cytokine, Mechanistic studies

Received: 23 Oct 2018; Accepted: 06 Mar 2019.

Edited by:

Denise Doolan, Australian Institute of Tropical Health and Medicine, Division of Tropical Health and Medicine, James Cook University, Australia

Reviewed by:

Steven Varga, The University of Iowa, United States
Randy A. Albrecht, Icahn School of Medicine at Mount Sinai, United States  

Copyright: © 2019 Li, Russell, Creskey, muralidharan, Li, Gao, Chen, Larocque, Lavoie, Farnsworth, Rosu-Myles, Yauk, Cao, Van Domselaar and Cyr. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Sean (Xuguang) Li, Health Canada, Ottawa, K1A 0K9, Ontario, Canada, sean.li@hc-sc.gc.ca